An Efficient Method for the Conjugation of Hydrophilic and Hydrophobic Components by Solid‐Phase‐Assisted Disulfide Ligation

Abstract

Chemical conjugation between hydrophilic and hydrophobic components is difficult because of their extremely different solubility. Herein, we report a new versatile method with a solid-phase-assisted disulfide ligation to overcome the difficulty of conjugation attributed to solubility. The method involves two steps in a one-pot process: 1) loading of a hydrophobic molecule onto a resin in an organic solvent, and 2) release of the solid-supported hydrophobic molecule as a conjugate with a hydrophilic molecule into an aqueous solvent. This strategy allows the use of a suitable solvent system for the substrates in each step. Conjugates of a water-insoluble drug, plinabulin, with hydrophilic carriers that could not be prepared by solution-phase reactions were obtained in moderate yields (29-45 %). This strategy is widely applicable to the conjugation of compounds with solubility problems.

Cyclic Dipeptide: A Privileged Molecular Scaffold to Derive Structural Diversity and Functional Utility

“…These results suggest that the observed cytotoxicity is attributed to the availability of plinabulin ( 11 ) in cells after enzymatic cleavage of the peptide. In order to boost the practical utility of water soluble pro‐drugs, a simplified synthetic methodology for the ligation of various water soluble and target specific ligands to the plinabulin with enhanced yields has been developed (Scheme 2C) [84] . The synthetic methodology involves the preparation of monolactim derivative of plinabulin followed by ligation to 3‐nitro‐2‐pyridinesulfenyl resin (Npys) in organic solvent.…”

“…In order to boost the practical utility of water soluble pro-drugs, a simplified synthetic methodology for the ligation of various water soluble and target specific ligands to the plinabulin with enhanced yields has been developed (Scheme 2C). [84] The synthetic methodology involves the preparation of monolactim derivative of plinabulin followed by ligation to 3-nitro-2pyridinesulfenyl resin (Npys) in organic solvent. In the next step, plinabulin attached to resin was reacted with hydrophilic thiol ligands in aqueous solvent to obtain the target pro-drugs.…”

Establishment of One-Pot Disulfide-Driven Cyclic Peptide Synthesis with a 3-Nitro-2-pyridinesulfenate

“…A component A, containing a t-Bu-protected thiol is loaded onto Npys-resin via an active disulfide. After washing the resin, a disulfide exchange reaction between an unprotected thiol-containing component B and an active disulfide on the resin results in efficient production in solution of a compound with a disulfide connection between the two components with high purity, whereas unreacted active disulfide and thiopyridone by-product are remaining on the resin [9][10][11] (Chart S1 in Supplementgary Materials).…”

Disulfide-Driven Cyclic Peptide Synthesis of Human Endothelin-2 with a Solid-Supported Npys-Cl

“…This strategy consists of two steps: (1) disulfide bond formation between two sulfur-containing peptide fragments to afford a disulfide peptide and (2) subsequent intramolecular cyclization of the disulfide peptide via regioselective amide bond formation. To ensure that the first step is efficient and simple, we used 3-nitro-2-pyridinesulfenyl (Npys) chemistry and developed a new Npys-Cl resin. This resin enables the one-pot solid-phase disulfide ligation (SPDSL) , shown in Figure .…”